PDF(Pubmed)
Abstract：
The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.
摘要：
胃源激素ghrelin调节基本生理功能。生长素释放肽受体（GHSR）具有不依赖配体的作用；因此，GHSR基因缺失可能是研究该系统在喂养行为和饮食诱导的肥胖（DIO）中的作用的合理方法。这里,我们研究了长期(12个月)高脂肪(HFD)与常规饮食对全球GHSR-KO和野生型(WT)Wistar雄性和雌性大鼠肥胖相关指标的影响.我们的主要发现是，GHSR基因缺失可以保护雄性大鼠在HFD期间抵抗DIO并减少食物摄入，而不是雌性大鼠。GHSR基因缺失可增加雄性大鼠的产热和脑葡萄糖摄取，并以性别特异性方式改变HFD对脑葡萄糖代谢的影响。如用小动物正电子发射断层扫描评估。我们使用RNA测序显示GHSR-KO大鼠在棕色脂肪组织中上调了负责脂肪氧化的基因表达。新型GHSR反向激动剂的中央管理，PF-5190457，减弱生长素释放肽诱导的食物摄入，但只有男性，不是在雌性老鼠身上。HFD诱导的暴饮暴食可通过两性的反向激动来减少。我们的结果支持GHSR作为肥胖新药物疗法的有希望的靶标。
